Diabetes is one of the leading causes of death in the United States and a well-recognized independent risk factor for the development of cardiovascular (CV) and end-stage renal disease in premenopausal and postmenopausal women. Diabetic women exhibit a greater prevalence of cardiovascular and renal pathologies as compared to age-matched males or non-diabetic females. The recent classification of cardiorenal syndrome in diabetic patients emphasizes the occurrence of simultaneous injury and/or dysfunction in the heart and kidney. Importantly, the combined renal and cardiac dysfunction or failure in diabetic hypertensive women with estrogen depletion significantly contributes to the poor prognosis for these patients. The absence of an in vivo experimental model of cardiorenal syndrome in hypertensive diabetic females limits our ability to elucidate the underlying mechanisms of this syndrome, as well as the development of more effective therapeutic approaches. This application seeks to establish an experimental model of diabetic cardiorenal syndrome in the congenic mRen2.Lewis rat that reflects the coexistence of cardiac and renal dysfunction/failure in diabetic hypertensive women with reduced estrogen. The studies will also establish the role of the novel estrogen receptor GPR30 to attenuate the development and progression of the cardiorenal syndrome which may reveal new therapeutic approaches to reduce CV disease in women. PUBLIC HEALTH RELEVANCE: Cardiovascular disease (CVD) is leading cause of death for women in the US and the identification of the cardiorenal syndrome (the interrelationship between cardiac and renal dysfunction) may have important implications regarding the early diagnosis and treatment of CVD in women, particularly with diabetes as an additional complicating factor. The proposed project addresses a critical issue in the cardiorenal syndrome through the development of a robust experimental model in the diabetic hypertensive mRen2.Lewis strain and assessment of the novel estrogen receptor GPR30.